The use of molecular orbital indices to predict the surface properties of pharmaceutical powders

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The electron density, frontier electron density and superdelocalisability indices have been calculated for the total molecular structures, and the parts of the molecules which are anticipated to be involved in hydrogen bonding interactions. The models used comprised of an homologous series (alkyl P-hydroxybenzoates), materials related by a common ring structure, but with differing substituents (imidazoles), and three related comparatively large molecular weight drugs (HMG-CoA reductase inhibitors). Surface energies were determined from contact angle data with water, using Neumann's equation of state. No relationship was seen between data for total molecular orbital indices for the molecules and measured contact angles or derived surface energies. However, when the hydrogen bonding atoms of the molecules were selected, a good linear correlation was observed for all three types of molecule between superdelocalisability and both contact angle and surface energy. This is expected as the hydrogen bonding regions are probably especially important in interactions with water. Two (of 16) molecules were outliers from the general relationship. These were one of the HMG-CoA reductase inhibitors and methyl p-hydroxybenzoate. It is possible that the high molecular weight of the first of these molecules was the cause of an error in calculation of the molecular orbital indices (due to optimisation to a secondary minimum). For the methyl P-hydroxybenzoate, there are considerable data in the literature to indicate that this material has idiosyncratic properties. Its curious behaviour is examined with consideration to possible crystal packing energy differences over other members in the series. The data presented here give encouragement that the surface properties of a wide range of different materials may be predicted from molecular structure, however, there are inevitable outliers which will mean that predictions will have to be confirmed with practical observations, until modelling approaches have been developed further and adequately validated.